Comparative Efficacy of High-Dose Dexamethasone Versus Methylprednisolone in Coronavirus Disease 2019 (COVID-19)-Associated Acute Respiratory Distress Syndrome.

OBJECTIVE: This retrospective (matched paired) clinical trial aimed to compare the efficacy of dexamethasone vs. methylprednisolone at equipotent (high) doses in patients with coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome (ARDS). METHODS: A total of 347 patients with moderate and severe COVID-19-associated ARDS were administered either a high (equipotent) dose of dexamethasone (32 mg) or methylprednisolone (180 mg) for a duration of up to 10 days. All participants received the standard of care for critically ill COVID-19 patients. RESULTS: The primary outcomes included length of stay in the ICU, ICU mortality, and discharge from the hospital. Based on the obtained results, a tendency towards more favorable clinical outcomes concerning the length of stay in the ICU (in the group of patients treated with non-invasive mechanical ventilation (NIV), p<0.05), ICU mortality, and discharge from the hospital (in the group of patients who were intubated, p<0.05) in patients receiving the high dose of dexamethasone compared to those receiving methylprednisolone was observed. CONCLUSION: It appears that severe cases of COVID-19, especially intubated ones, treated with high doses of dexamethasone have a more favorable clinical outcome than the use of equipotent doses of methylprednisolone. However, larger multicenter studies are needed to validate our observations.

Beneficial Effects of Ursodeoxycholic Acid on Metabolic Parameters and Oxidative Stress in Patients with Type 2 Diabetes Mellitus: A Randomized Double-Blind, Placebo-Controlled Clinical Study.

Background: Oxidative stress and inflammation are closely related pathophysiological processes, both occurring in type 2 diabetes mellitus (T2DM). In addition to the standard treatment of T2DM, a potential strategy has been focused on the use of bile acids (BAs) as an additional treatment. Ursodeoxycholic acid (UDCA), as the first BA used in humans, improves glucose and lipid metabolism and attenuates oxidative stress. The aim of this study was to evaluate the potential metabolic, anti-inflammatory, and antioxidative effects of UDCA in patients with T2DM. Methods: This prospective, double-blind, placebo-controlled clinical study included 60 patients with T2DM, randomly allocated to receive UDCA or placebo. Subjects were treated with 500 mg tablets of UDCA or placebo administered three times per day (total dose of 1500 mg/day) for eight weeks. Two study visits, at the beginning (F0) and at the end (F1) of the study, included the interview, anthropometric and clinical measurements, and biochemical analyses. Results: UDCA treatment showed a significant reduction in body mass index (p = 0.024) and in diastolic blood pressure (p = 0.033), compared to placebo. In addition, there was a statistically significant difference in waist circumference in the UDCA group before and after treatment (p < 0.05). Although no statistical significance was observed at the two-month follow-up assessment, an average decrease in glucose levels in the UDCA group was observed. After two months of the intervention period, a significant decrease in the activity of liver enzymes was noticed. Furthermore, a significant reduction in prooxidative parameters (TBARS, NO2-, H2O2) and significant elevation in antioxidative parameters such as SOD and GSH were found (p < 0.001). Conclusions: The eight-week UDCA administration showed beneficial effects on metabolic and oxidative stress parameters in patients with T2DM. Thus, UDCA could attenuate the progression and complications of diabetes and should be considered as an adjuvant to other diabetes treatment modalities. This trial is registered with NCT05416580.

Effect of folic acid on isoprenaline-induced myocardial injury in rats.

Background: Isoprenaline (ISO), a synthetic catecholamine and a ß-adrenoceptor agonist, is widely used to develop an experimental model of myocardial injury (MI) in rats. The leading hypothesis for ISO-induced MI in rats is that it results from catecholamine overstimulation, oxidative stress, inflammatory responses, and development of cardiomyopathy during ISO administration. Folic acid (FA) reduces oxidative stress, improves endothelial function and prevents apoptosis, thereby contributing to cardiovascular protection. This study aimed to investigate the potentially protective effect of FA pretreatment on ISO-induced MI in rats. Methods: For 7 days, adult male Wistar albino rats were pretreated with 5 mg/kg/day of FA. On the sixth and seventh days, MI in rats was induced by administering 85 mg/kg/day of ISO. Prooxidant markers in plasma samples, antioxidant capacity in erythrocyte lysates, cardiac damage markers, lipid profile, electrocardiography (ECG) and histopathological analysis were evaluated. Results: FA pretreatment significantly alleviated changes induced by ISO; it decreased the homocysteine and high-sensitivity troponin I level. FA moderately decreased the reactive oxygen species (ROS) levels (superoxide anion radical, hydrogen peroxide and thiobarbituric acid reactive substances) and improved the antioxidant activities of catalase, superoxide dismutase and reduced glutathione. ISO reduced the nitrite level and FA significantly alleviated this change. Conclusion: It can be concluded that FA, as a mild antioxidant, could be an appropriate cardioprotective substance in the rat model of ISO-induced MI.

Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta.

Hypotensive influences of benzodiazepines and other GABAA receptor ligands, recognized in clinical practice, seem to stem from the existence of "vascular" GABAA receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABAA receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABAA γ2 and α1-5 subunit proteins. To confirm the role of "vascular" GABAA receptors, we investigated the vascular effects of standard benzodiazepines, midazolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5ß3γ2 over other αxß3γ2 GABAA receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazolam, both of which at 100 µmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABAA receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators.

Analysis of redox status and HDL subclasses in patients with lymphoma and the associations with FDG-PET/CT findings.

Newer research points to alterations in the plasma redox status and the HDL subclass distributions in cancer. We aimed to assess the redox status and the HDL subclass distributions, lipids, and inflammatory markers in lymphoma patients in order to determine whether they were correlated with changes in FDG-PET/CT scans. At the beginning of this study, redox status, HDL subclasses, lipids, and inflammation biomarkers were determined in 58 patients with lymphoma (Hodgkin lymphoma, n=11 and non-Hodgkin lymphoma, n=47), and these same measurements were reassessed during their ensuing treatment (in 25 patients). Initially, the total oxidation status (TOS), the prooxidant-antioxidant balance (PAB), the OS index (OSI), the total protein sulfhydryl groups (SH-groups), and the advanced oxidation protein products (AOPP) were significantly higher in lymphoma patients as compared to healthy subjects, but the total antioxidant status (TAS) was significantly reduced. The PAB had a strong correlation with the CRP and interleukin-6 (rho=0.726, p<0.001; rho=0.386, p=0.003). The correlations between these parameters and the maximum standardized uptake values (SUVmax) were: PAB, rho=0.335 and p=0.010; SH-groups, rho=0.265 and p=0.044; CRP, rho=0.391 and p=0.002; HDL3b, rho=0.283 and p=0.031; HDL2b, rho= -0.294 and p=0.025; and HDL size, rho= -0.295 and p=0.024. The reductions in SUVmax between two follow-up points were associated with increases in the OSI, TOS, and SH-groups, as well as a reduction in the PAB and TAS. In conclusion, the redox parameters in patients with lymphoma were consistent with FDG-PET/CT findings. Targeting the redox status parameters and the HDL subclasses could be potential strategies in the molecular fight against lymphoma.

Methodological challenges in using human umbilical artery as a model for in vitro studies.

NEW FINDINGS: What is the central question of this study? What are the biggest challenges in performing in vitro studies on isolated human umbilical arteries? What is the main finding and its importance? The protocols presented in this study indicate some potential outcomes important for interpretation of the vascular responsivities of human umbilical arteries and could be useful for planning future in vitro studies with human umbilical arteries. ABSTRACT: Human umbilical artery (HUA) preparations are of particular importance for in vitro studies on isolated blood vessels because their sampling is not risky for the patient, and they can provide the closest possible impression of changes related to the uteroplacental circulation during pre-eclampsia. Using organ bath techniques, useful experimental protocols are provided for measuring some pathophysiological phenomena in the vascular responses of HUAs. Several vasoconstrictors (serotonin, prostaglandin F and phenylephrine) and vasodilators (acetylcholine and minoxidil) were seleted for determination of their vasoactivity in HUAs. The role of L-type voltage-operated calcium channels and different types of potassium channels (KATP , BKCa and KV ) were assessed, as was the impact of homocysteine. Serotonin was confirmed to be the most potent vasoconstrictor, while acetylcholine and phenylephrine caused variability in the relaxation and contraction response of HUA, respectively. The observed increase in serotonin-induced contraction and a decrease in minoxidil-induced relaxation in the presence of homocysteine suggested its procontractile effect on HUA preparations. Using selective blockers, it was determined that KATP and KV channels participate in the minoxidil-induced relaxation, while L-type voltage-dependent Ca2+  channels play an important role in the serotonin-induced contraction. The presented protocols reveal some of the methodological challenges related to HUA preparations and indicate potential outcomes in interpreting the vascular effects of the investigated substances, both in physiological conditions and in the homocysteine-induced pre-eclampsia model.

Pomegranate Peel Extract Differently Modulates Gene Expression in Gingiva-Derived Mesenchymal Stromal Cells under Physiological and Inflammatory Conditions.

Pomegranate has shown a favorable effect on gingivitis/periodontitis, but the mechanisms involved are poorly understood. The aim of this study was to test the effect of pomegranate peel extract (PoPEx) on gingiva-derived mesenchymal stromal cells (GMSCs) under physiological and inflammatory conditions. GMSC lines from healthy (H) and periodontitis (P) gingiva (n = 3 of each) were established. The lines were treated with two non-toxic concentrations of PoPEX (low-10; high-40 µg/mL), with or without additional lipopolysaccharide (LPS) stimulation. Twenty-four genes in GMSCs involved in different functions were examined using real-time polymerase chain reaction (RT-PCR). PoPEx (mostly at higher concentrations) inhibited the basal expression of IL-6, MCP-1, GRO-α, RANTES, IP-10, HIF-1α, SDF-1, and HGF but increased the expression of IL-8, TLR3, TGF-ß, TGF-ß/LAP ratio, IDO-1, and IGFB4 genes in H-GMSCs. PoPEx increased IL-6, RANTES, MMP3, and BMP2 but inhibited TLR2 and GRO-α gene expression in P-GMSCs. LPS upregulated genes for proinflammatory cytokines and chemokines, tissue regeneration/repair (MMP3, IGFBP4, HGF), and immunomodulation (IP-10, RANTES, IDO-1, TLR3, COX-2), more strongly in P-GMSCs. PoPEx also potentiated most genes' expression in LPS-stimulated P-GMSCs, including upregulation of osteoblastic genes (RUNX2, BMP2, COL1A1, and OPG), simultaneously inhibiting cell proliferation. In conclusion, the modulatory effects of PoPEx on gene expression in GMSCs are complex and dependent on applied concentrations, GMSC type, and LPS stimulation. Generally, the effect is more pronounced in inflammation-simulating conditions.

GPX3 rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy.

Current data suggest that aristolochic acid (AA) exposure is a putative cause of Balkan endemic nephropathy (BEN), a chronic kidney disease strongly associated with upper tract urothelial carcinoma. The cellular metabolism of AA is associated with the production of reactive oxygen species, resulting in oxidative distress. Purpose: Therefore, the aim of this study was to analyze individual, combined and cumulative effect of antioxidant gene polymorphisms (Nrf2 rs6721961, KEAP1 rs1048290, GSTP1AB rs1695, GSTP1CD rs1138272, GPX3 rs8177412 and MDR1 rs1045642), as well as GSTP1ABCD haplotypes with the risk for BEN development and associated urothelial cell carcinoma in 209 BEN patients and 140 controls from endemic areas. Experimental method: Genotyping was performed using polymerase chain reaction (PCR) and PCR with confronting two-pair primers (PCR-CTTP) methods. Results: We found that female patients carrying both variant GPX3 rs8177412 and MDR1 rs1045642 genotypes in combination exhibited significant risk towards BEN (OR 1 = 3.34, 95% CI = 1.16-9.60, p = 0.025; OR 2 = 3.79, 95% CI = 1.27-11.24, p = 0.016). Moreover, significant association was determined between GPX3rs8174412 polymorphism and risk for urothelial carcinoma. Carriers of variant GPX3*TC + CC genotype were at eight-fold increased risk of BEN-associated urothelial tumors development. There was no individual or combined impact on BEN development and BEN-associated tumors among all examined polymorphisms. The haplotype consisting of variant alleles for both polymorphisms G and T was associated with 1.6-fold increased risk although statistically insignificant (OR = 1.64; 95% CI = 0.75-3.58; p = 0.21). Conclusions: Regarding GPX3 rs8177412 polymorphism, the gene variant that confers lower expression is associated with significant increase in upper urothelial carcinoma risk. Therefore, BEN patients carrying variant GPX3 genotype should be more frequently monitored for possible upper tract urothelial carcinoma development.

Overexpression of MRP1/ABCC1, Survivin and BCRP/ABCC2 Predicts the Resistance of Diffuse Large B-Cell Lymphoma to R-CHOP Treatment.

BACKGROUND: Approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience treatment resistance to the first-line R-CHOP regimen. ATP binding cassette (ABC) transporters and survivin might play a role in multidrug resistance (MDR) in various tumors. The aim was to investigate if the coexpression of ABC transporters and survivin was associated with R-CHOP treatment response. METHODS: The expression of Bcl-2, survivin, P-glycoprotein/ABCB1, MRP1/ABCC1, and BCRP/ABCC2 was analyzed using immunohistochemistry in tumor specimens obtained from patients with DLBCL, and classified according to the treatment response as Remission, Relapsed, and (primary) Refractory groups. All patients received R-CHOP or equivalent treatment. RESULTS: Bcl-2 was in strong positive correlation with clinical parameters and all biomarkers except P-gp/ABCB1. The overexpression of MRP1/ABCC1, survivin, and BCRP/ABCC2 presented as high immunoreactive scores (IRSs) was detected in the Refractory and Relapsed groups (p < 0.05 vs. Remission), respectively, whereas the IRS of P-gp/ABCB1 was low. Significant correlations were found among either MRP1/ABCC1 and survivin or BCRP/ABCC2 in the Refractory and Relapsed groups, respectively. In multiple linear regression analysis, ECOG status along with MRP1/ABCC1 or survivin and BRCP/ABCG2 was significantly associated with the prediction of the R-CHOP treatment response. CONCLUSIONS: DLBCL might harbor certain molecular signatures such as MRP1/ABCC1, survivin, and BCRP/ABCC2 overexpression that can predict resistance to R-CHOP.

Eleven-Year Trends in Lipid-Modifying Medicines Utilisation and Expenditure in a Low-Income Country: A Study from the Republic of Srpska, Bosnia and Herzegovina.

Background: In last two decades, there have been substantial changes in the pattern of lipid-modifying medicines utilisation following the new treatment guidelines based on clinical trials. The main purpose of this study was to analyse the overall utilisation and expenditure of lipid-modifying medicines in the Republic of Srpska, Bosnia and Herzegovina during an 11-year follow-up period and to express its share in relation to the total cardiovascular medicines (C group) utilisation. Methods: In this retrospective, observational study, medicines utilisation data were analysed between 2010 and 2020 period using the ATC/DDD methodology and expressed as the number of DDD/1000 inhabitants/day (DDD/TID). The medicines expenditure analysis was used to estimate the annual expenditure of medicines in Euro based on DDD. Results: During the analysed period, the use of lipid-modifying medicines increased almost 3-times (12.82 DDD/TID in 2010 vs 34.32 DDD/TID in 2020), with a rise in expenditure from 1.24 million Euro to 2.15 million Euro in the same period. This was mainly driven by an increased use of statins with 163.07%, and among these, rosuvastatin increased more than 1500-fold, and atorvastatin with 106.95% increase. With the appearance of generics, simvastatin showed a constant decline, while the other lipid-modifying medicines in relation to the total utilisation had a neglecting increase. Conclusion: The use of lipid-modifying medicines in the Republic of Srpska has constantly increased and strongly corresponded to the adopted treatment guidelines and the positive medicines list of health insurance fund. The results and trends are comparable with other countries, but still the utilisation of lipid-lowering medicines represents the smallest share of total medicines use for the treatment of cardiovascular diseases, compared to high-income countries.

Pomegranate Peel Extract Attenuates Isoprenaline-Induced Takotsubo-like Myocardial Injury in Rats.

Takotsubo syndrome (TTS) is an acute heart failure syndrome characterised by catecholamine-induced oxidative tissue damage. Punica granatum, a fruit-bearing tree, is known to have high polyphenolic content and has been proven to be a potent antioxidant. This study aimed to investigate the effects of pomegranate peel extract (PoPEx) pre-treatment on isoprenaline-induced takotsubo-like myocardial injury in rats. Male Wistar rats were randomised into four groups. Animals in the PoPEx(P) and PoPEx + isoprenaline group (P + I) were pre-treated for 7 days with 100 mg/kg/day of PoPEx. On the sixth and the seventh day, TTS-like syndrome was induced in rats from the isoprenaline(I) and P + I groups by administering 85 mg/kg/day of isoprenaline. PoPEx pre-treatment led to the elevation of superoxide dismutase and catalase (p < 0.05), reduced glutathione (p < 0.001) levels, decreased the thiobarbituric acid reactive substances (p < 0.001), H2O2, O2- (p < 0.05), and NO2- (p < 0.001), in the P + I group, when compared to the I group. In addition, a significant reduction in the levels of cardiac damage markers, as well as a reduction in the extent of cardiac damage, was found. In conclusion, PoPEx pre-treatment significantly attenuated the isoprenaline-induced myocardial damage, primarily via the preservation of endogenous antioxidant capacity in the rat model of takotsubo-like cardiomyopathy.

The role of high-income countries in the establishment and development of modern critical care in low resource settings: A Slovenian model.

BACKGROUND: Critical care medicine is a young branch of medicine, of which the development was much faster in High Income Countries (HICs) than in Low Resources Settings (LRS). Slovenia, as one of the successor states of former Yugoslavia, passed the process of transition and joined the European Union successfully. On the contrary, Bosnia and Herzegovina (B&H) went through the extremely difficult process of transition (four years of civil war), which left a deep scar to the healthcare system, including critical care medicine. OBJECTIVE: To examine the impact of HICs on the development of critical care in LRS. METHOD: This review examined the process of growing up the first modern Medical Intensive Care Unit (MICU) in the Republic of Srpska. RESULTS: The five-year process of transferring critical care knowledge from Slovenia to the health care system of Republic of Srpska has contributed to the existence of modern and state of the art MICU with tremendous social effects. CONCLUSION: The model of using the impact of HICs for improving critical care in LRS can be extrapolated to other similar settings.

The comparison of SARS-CoV-2 antibody levels in medical personnel induced by different types of vaccines compared to the natural infection.

INTRODUCTION: During the last two and a half years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread around the world. Most of the SARS-CoV-2 vaccines are designed to produce anti-SARS-CoV-2 immunoglobulin G (IgG) against the viral S-glycoprotein. The aim of this study was to measure the anti-S antibody titres among the medical personnel who had been fully vaccinated with different types of vaccines, and to compare them with those who were COVID-19 convalescents. MATERIAL AND METHODS: In this study serum was collected from 261 healthcare workers, of whom 227 were vaccinated, while 34 were recovered participants who were not immunised. Serum samples were collected 21 days after the first dose and 60 and 180 days after the second dose of the vaccines and tested with a commercial ELISA kit. RESULTS: The highest antibody level (12 AU/ml) was measured in the Pfizer-BioNTech group, followed by Sinopharm (9.3 AU/ml), Sputnik V (5.9 AU/ml), Sinovac (4.6 AU/ml) and Oxford/Astra- Zeneca vaccine (2.5 AU/ml) 60 days after the second dose of the vaccines (90 days after the first dose). The seropositivity rate for mRNA vaccine was 88.5%, for vector vaccines 86.2% and for inactivated vaccines 71.4%. When comparing these antibody levels with COVID-19 convalescents, higher antibody titres were found in vaccinated participants (5.76 AU/ml vs 7.06 AU/ml), but the difference was not significant (p = 0.08). CONCLUSIONS: Individuals vaccinated with mRNA and vector vaccines had a higher seroconversion rate compared to the group vaccinated with inactivated vaccines, or convalescents.

Folic Acid and Leucovorin Have Potential to Prevent SARS-CoV-2-Virus Internalization by Interacting with S-Glycoprotein/Neuropilin-1 Receptor Complex.

The interaction of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain with the host-cell ACE2 receptor is a well-known step in virus infection. Neuropilin-1 (NRP-1) is another host factor involved in virus internalization. The interaction between S-glycoprotein and NRP-1 has been identified as a potential COVID-19 treatment target. Herein, the effectiveness of folic acid and leucovorin in preventing contact between S-glycoprotein and NRP-1 receptors was investigated using in silico studies and then confirmed in vitro. The results of a molecular docking study showed that leucovorin and folic acid had lower binding energies than EG01377, a well-known NRP-1 inhibitor, and lopinavir. Two hydrogen bonds with Asp 320 and Asn 300 residues stabilized the leucovorin, while interactions with Gly 318, Thr 349, and Tyr 353 residues stabilized the folic acid. The molecular dynamic simulation revealed that the folic acid and leucovorin created very stable complexes with the NRP-1. The in vitro studies showed that the leucovorin was the most active inhibitor of the S1-glycoprotein/NRP-1 complex formation, with an IC75 value of 185.95 µg/mL. The results of this study suggest that folic acid and leucovorin could be considered as potential inhibitors of the S-glycoprotein/NRP-1 complex and, thus, could prevent the SARS-CoV-2 virus' entry into host cells.

Antibiotic Utilization during COVID-19: Are We Over-Prescribing?

The aims of this study were to analyze the utilization of antibiotics before (2018, 2019) and during the COVID-19 pandemic (2020) and the practice of prescribing antibiotics in outpatient settings for COVID-19 patients during the 2020-2022 period. The Anatomical Therapeutic Chemical Classification/Defined Daily Dose methodology was used for the analysis of outpatient antibiotic utilization in the Republic of Srpska. The data was expressed in DDD/1000 inhabitants/day. The rate of antibiotics prescribed to COVID-19 outpatients was analyzed using medical record data from 16,565 patients registered with B34.2, U07.1, and U07.2 World Health Organization International Classification of Diseases 10th revision codes. During 2020, outpatient antibiotic utilization increased by 53.80% compared to 2019. At least one antibiotic was prescribed for 91.04%, 83.05%, and 73.52% of COVID-19 outpatients during 2020, 2021, and the first half of 2022, respectively. On a monthly basis, at least one antibiotic was prescribed for more than 55% of COVID-19 outpatients. The three most commonly prescribed antibiotics were azithromycin, amoxicillin/clavulanic acid, and doxycycline. The trend of repurposing antibiotics for COVID-19 and other diseases treatment might be a double-edged sword. The long-term effect of this practice might be an increase in antimicrobial resistance and a loss of antibiotic effectiveness.

Cardioprotective effects of liraglutide pretreatment on isoprenaline-induced myocardial injury in rats.

Type 2 diabetes mellitus (T2DM) increases the risk of cardiovascular disease, especially myocardial injury. Due to their hypoglycemic effects, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are efficiently used for T2DM management. GLP-1RAs also have anti-inflammatory and antioxidative effects and can improve cardiac function. The aim of this study was to investigate the cardioprotective effects of liraglutide, a GLP-1RA, on isoprenaline-induced myocardial injury in rats. The study included four groups of animals. They were pretreated with saline for 10 days + saline on days 9 and 10 (control), saline for 10 days + isoprenaline on days 9 and 10 (isoprenaline group), liraglutide for 10 days + saline on days 9 and 10 (liraglutide group), and liraglutide for 10 days, and on days 9 and 10 isoprenaline was administered. This study evaluated ECG, myocardial injury markers, oxidative stress markers, and pathohistological changes. The results showed that liraglutide mitigated the isoprenaline-induced cardiac dysfunction recorded by ECG. Liraglutide reduced serum markers of myocardial injury such as high-sensitive troponin I, aspartate aminotransferase, alanine aminotransferase, reduced thiobarbituric acid reactive substances, increased catalase and superoxide dismutase activity, increased reduced glutathione level, and improved lipid profile. Liraglutide induced antioxidative protection and alleviated isoprenaline-induced myocardial injury.

Pulsed electromagnetic field attenuates bone fragility in estrogen-deficient osteoporosis in rats.

BACKGROUND: The pulsed electromagnetic fields (PEMFs) seem effective in increasing bone mineral density and promoting osteogenesis and bone healing. OBJECTIVE: To examine the effect of two different modalities of PEMFs therapy in comparison with the recommended pharmacological treatment on experimental osteoporosis in rats. METHODS: The experimental model of estrogen-deficient osteoporosis induced by ovariectomy was used in this study. The animals were exposed to PEMFs of various frequencies (40 Hz and 25 Hzk), intensities (10 mT and 36.4 µT), lengths of exposure, and the effects were compared with the standard treatment with pamidronate, vitamin D, and calcium supplementation. RESULTS: The application of PEMF40Hz, significantly reduced the osteoporotic bone loss in female rats that were confirmed with biochemical, biomechanical, and histological analyses. These effects were more pronounced than in osteoporotic animals treated with pamidronate, vitamin D, and calcium supplementation. On the contrary, the exposure to PEMF25Hz did not show restorative effects but led to further progression of osteoporosis. CONCLUSION: The exposure to PEMF40Hz, significantly restored osteoporosis and attenuated bone fragility in comparison to the rats exposed to PEMF25Hz or those treated with pamidronate, vitamin D, and calcium supplementation.

Boosting ICU capacity during the COVID-19 pandemic in the western Balkan region, The Republic of Srpska experience.

Background: Response to the outbreak of poliomyelitis in mid-1950 led to recognition and consequent development of critical care. Seventy years later the humankind was struck by COVID-19, another major challenge for critical care medicine which was especially big in Low-Resources-Settings where more than two thirds of the world population live, including the population of the Republic of Srpska (RS). Design and methods: The main aim was to show an overview of all interventions in order to boost hospitals' capacities to the level which is sufficient to manage high amount of critically ill COVID-19 patients in the RS. A before-after cohort study design was conducted to evaluate the effects of interventions for increase in preparedness and capacity of ICUs for admission and treatment of COVID-19 critically ill patients in nine hospitals in the RS. Results: Following interventions, the biggest and university affiliated hospital in the RS has increased ICU capacities: total number of ICU beds increased by 38% and number of ventilators by 114%. Availability of machines for veno-venous extracorporeal membrane oxygenation (vvECMO) increased by 100%. Number of doctors who were involved in treatment of critically ill patients increased by 47% and nurse/patient's ratio reached 1:2.5. Similarly, all other hospitals experienced boosting of ICU beds by 189% and ventilators by 373% while number of doctors increased by 108% and nurse/patient's ratio reached 1:4. Conclusion: All interventions implemented during COVID-19 pandemic outbreak in the RS resulted in increasing capacity for treatment of critically ill patients, but the education of health care professionals was identified as the most important conducted intervention.

Dynamic changes in coagulation, hematological and biochemical parameters as predictors of mortality in critically ill COVID-19 patients: A prospective observational study.

INTRODUCTION: This study was created to analyze dynamic alterations in coagulation, hematological and biochemical parameters and their association with mortality of COVID-19 patients. To identify the most sensitive biomarkers as predictors of mortality more research is required. METHODS: The present study was a prospective, one-year-long observational study conducted on all critically ill, COVID-19 patients with respiratory failure. The following data were collected: demographic and clinical characteristics of the study population, comorbidities, coagulation, biochemical and hematological parameters. The primary outcome was the proportion of patients who died. RESULTS: 91 patients with median age 60 (50-67), 76.9% male, met the acute respiratory distress syndrome criteria. It was tested whether dynamic change (delta-Δ) of parameters that were found to be predictors of mortality is independently associated with poor outcome. Adjusted (multivariate) analysis was used, where tested parameters were corrected for basic and clinical patients characteristics. The only inflammatory parameter which dynamic change had statistically significant odds ratio was ΔCRP (p < 0.005), while among coagulation parameters statistically significant OR was found for Δ fibrinogen (p < 0.005) in predicting mortality. CONCLUSION: Monitoring of coagulation, hematological and biochemical parameters abnormalities and their dynamical changes can potentially improve management and predict mortality in critically ill COVID -19 patients.